In this .project, we have been testing the hypothesis that neuroinflammation contributes to neurodegeneration in vivo and that targeting selective glial activation pathways linked to disease-relevant endpoints will suppress neuroinflammation and provide neuroprotection. We emphasize throughout this application by concrete examples how our work has contributed to a better understanding of molecular mechanisms underlying neuroinflammation, how our in vivo studies have validated the relationship between chronic glial activation and neuronal dysfunction/death, and how our in vivo (integrated) chemical biology research has demonstrated that targeting neuroinflammatory signaling pathways is a viable approach to development of future therapeutics for Alzheimer's disease (AD). Our work over the last four years has contributed substantially to the increasing appreciation of the field that neuroinflammation plays a key role in the progression of pathology in neurodegenerative diseases, and we are committed and eager to continue our work in this area. Finally, MERIT grant awardees are expected to be leaders in their disciplines, and to increase their visibility and contributions to the field during the time of the award. During the last four years, I believe that this has been the case in terms of my contributions to the area of neuroinflammation and AD. The specific aims of the current funding period relate to this two-pronged research effort of defining mechanisms and developing strategies for modulation of glial activation. The goal of aim 1 was elucidation of molecular mechanisms of glial activation induced by beta-amyloid 1-42 (A(3) as the prototypical AD-relevant, glial activating stimulus. The goal of aim 2 was to develop strategies to modulate glial activation pathways that lead to detrimental responses and examine the consequences to neuronal function